VHL-Modified PROteolysis TArgeting Chimeras (PROTACs) as a Strategy to Evade Metabolic Degradation in <i>In Vitro</i> Applications

Castellani, Beatrice; Eleuteri, Michela; Di Bona, Stefano; Cruciani, Gabriele; Desantis, Jenny; Goracci, Laura

doi:10.1021/acs.jmedchem.3c01144

Cited by 3 publications

(1 citation statement)

References 69 publications

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“…To date, our group's interest in targeted protein degradation applied to different research fields 19–22 led us to synthesize a wide structurally heterogeneous library of more than 100 PROTACs. During the preparation of this library, we obtained consistently low yields, particularly in the last coupling synthetic amidation step, thus recognizing the need for exploring and identifying better reaction parameters/conditions.…”

Section: Introductionmentioning

confidence: 99%

Use of ionic liquids in amidation reactions for proteolysis targeting chimera synthesis

Eleuteri,

Desantis,

Cruciani

et al. 2024

Org. Biomol. Chem.

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Section: Introductionmentioning

confidence: 99%

Use of ionic liquids in amidation reactions for proteolysis targeting chimera synthesis

Eleuteri,

Desantis,

Cruciani

et al. 2024

Org. Biomol. Chem.

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Structure-Based Design of “Head-to-Tail” Macrocyclic PROTACs

Li,

Chen,

Huang

et al. 2024

JACS Au

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Macrocyclization is a compelling strategy for conventional drug design for improving biological activity, target specificity, and metabolic stability, but it was rarely applied to the design of PROTACs possibly due to the mechanism and structural complexity. Herein, we report the rational design of the first series of "Head-to-Tail" macrocyclic PROTACs. The resulting molecule SHD913 exhibited pronounced Brd4 protein degradation with low nM DC 50 values while almost totally dismissing the "hook effect", which is a general character and common concern of a PROTAC, in multiple cancer cell lines. Further biological evaluation revealed that the compound exhibited positive cooperativity and induced de novo protein−protein interactions (PPIs) in both biophysical and cellular NanoBRET assays and outperformed macroPROTAC-1 that is the first reported macrocyclic Brd4 PROTAC, in cellular assays. In vitro liver microsomal stability evaluation suggested that SHD913 demonstrated improved metabolic stability in different species compared with the linear counterpart. The co-crystal structure of Brd4 BD2 : SHD913: VCB (VHL, Elongin C and Elongin B) complex determination and molecular dynamics (MD) simulation also elucidated details of the chemical-induced PPIs and highlighted the crucial contribution of restricted conformation of SHD913 to the ternary complex formation. These results collectively support that macrocyclization could be an attractive and feasible strategy for a new PROTAC design.

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CRBN‐PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications

Thapa,

Bhat,

Gupta

et al. 2024

Chem Biol Drug Des

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Cereblon (CRBN), a member of the E3 ubiquitin ligase complex, has gained significant attention as a therapeutic target in cancer. CRBN regulates the degradation of various proteins in cancer progression, including transcription factors and signaling molecules. PROTACs (proteolysis‐targeting chimeras) are a novel approach that uses the cell's degradation system to remove disease‐causing proteins selectively. CRBN‐dependent PROTACs work by tagging harmful proteins for destruction through the ubiquitin–proteasome system. This strategy offers several advantages over traditional protein inhibition methods, including the potential to overcome drug resistance. Recent progress in developing CRBN‐based PROTACs has shown promising preclinical results in both hematologic malignancies and solid tumors. Additionally, CRBN‐based PROTACs have enhanced our understanding of CRBN's role in cancer, potentially serving as biomarkers for patient stratification and predicting therapeutic responses. In this review, we delineate the mechanisms of action for CRBN‐dependent PROTACs (CRBN‐PROTACs), summarize recent advances in preclinical and clinical applications, and provide our perspective on future development.

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VHL-Modified PROteolysis TArgeting Chimeras (PROTACs) as a Strategy to Evade Metabolic Degradation in In Vitro Applications

Cited by 3 publications

References 69 publications

Use of ionic liquids in amidation reactions for proteolysis targeting chimera synthesis

Use of ionic liquids in amidation reactions for proteolysis targeting chimera synthesis

Structure-Based Design of “Head-to-Tail” Macrocyclic PROTACs

CRBN‐PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications

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